Breast Cancer-free Survival Research Articles

Can dedicated breast PET help to reduce overdiagnosis and overtreatment by differentiating between indolent and potentially aggressive ductal carcinoma in situ?

To analyze the utility of metabolic imaging, and specifically of dedicated breast positron emission tomography (dbPET) to differentiate between indolent and potentially aggressive ductal carcinoma in situ (DCIS). After institutional review board approval, we retrospectively reviewed the cases of pure DCIS who underwent dbPET before biopsy and surgery in Lucus Augusti Universitary Hospital (Lugo, Spain) and in Fudan Cancer Institute (Shanghai, China) between January 2016 and May 2018. Grade 1 and "non-comedo" grade 2 DCIS were considered low-risk disease, while intermediate-grade with necrosis or grade 3 cases were included in the high-risk group. DbPET sensitivity and specificity to differentiate between indolent and potentially aggressive DCIS were determined along with their respective 95% confidence intervals. We enrolled 139 surgery-confirmed pure DCIS cases. Fifty were high-risk neoplasms and 89 low-risk DCIS. Only seven low-risk lesions were positive at dbPET and five of potentially aggressive neoplasms did not show FDG uptake, all included into the field of view (FOV). Sensitivity and specificity of dbPET to differentiate between indolent and potentially aggressive DCIS were 90% (95% CI, 77-96%) and 92% (95% CI, 84-97%), respectively. Metabolic imaging could help to identify the subgroup of indolent lesions from those potentially aggressive ones that may be managed by active surveillance. • Low- and high-grade DCIS likely arise from two distinct evolutionary paths and when low-grade lesions progress to invasive cancer, the tumor is frequently low grade and well differentiated. • Ongoing clinical trials evaluate whether patients with low-risk DCIS could be safely managed by an active surveillance approach, with avoidance of unnecessary treatments and without impact on ipsilateral invasive breast cancer free survival time. • Dedicated breast PET may differentiate harmless from potentially hazardous DCIS, supporting active surveillance for the management of those women with low-grade DCIS, decreasing the rate of the upgrade to invasive carcinoma at surgical excision.

Rethinking breast cancer surveillance in women with BRCA-associated ovarian cancer in the post-solo trial era.

5565 Background: Patients with BRCA mutations are at increased risk of developing both breast (BC) and epithelial ovarian cancer (EOC). Optimal breast cancer surveillance guidelines for BRCA mutation carriers following EOC has not been defined due to high risk of EOC recurrence. The recent SOLO-1 trial demonstrated a survival benefit of olaparib maintenance therapy for newly diagnosed women with advanced stage EOC. Olaparib reduced the risk of disease-progression or death by 70% compared to placebo with a median progression-free survival (PFS) of 36 months. Methods: An IRB-approved, multi-institutional study retrospective chart review was performed. Patients had BRCA-associated EOC diagnosed between 1990-2015 without a history of prior BC or mastectomy. All women received combination chemotherapy for EOC. The observed breast cancer free survival was adjusted to reflect the enhanced 3-year PFS observed in olaparib-treated women from the SOLO-1 trial. Kaplan-Meier survival curves were performed. Results: 191 patients with BRCA-associated EOC were included (135 BRCA1, 55 BRCA2, 1 BRCA1 and BRCA2). Median age was 53 years. Most women had advanced stage, high-grade serous EOC (75%). The median overall survival was 7.7 years for BRCA 1, and 9.7 years for BRCA2 mutation carriers. Annual mammography and MRI were performed in 43% and 34% of women, respectively, with a median of 4 mammograms and 3 MRI per patient. 16 women (8.3%) were diagnosed with BC over a median follow up of 80 months: 7 (44%) DCIS and 9 (56%) invasive ductal carcinoma. 14 (88%) women had early stage (0-2) BC. 28 (15%) of women had risk-reducing mastectomy performed an average of 2.1 years following their EOC diagnosis. The incidence of BC increased from 5.6% to 11% at 5- and 10-years post EOC, and in the predicted model with olaparib, from 10% to 17% at 5- and 10-years, assuming olaparib does not impact breast cancer incidence. Conclusions: The risk of metachronous BC following BRCA-associated EOC increases over time. In the post SOLO trial era, BC surveillance strategies in women with EOC should be optimized to reflect improved outcome. [Table: see text]

The CYP2C19 rs4917623 single nucleotide polymorphism to predict tamoxifen efficacy in estrogen receptor-positive breast cancer patients.

e12001 Background: Tamoxifen is a selective estrogen receptor modulator that is widely used to treat estrogen receptor (ER)-positive breast cancer. However, not all patients benefit from the incorporation of tamoxifen into an adjuvant therapy. This is also the case when tamoxifen is used in chemoprevention, since only half of participants benefit from the drug. In order to improve treatment response, we attempted to identify single nucleotide polymorphisms (SNPs) that correlated with tamoxifen efficacy. Methods: ER-positive breast cancer patients at our hospital were enrolled on this study between January 2007 and September 2010. The primary endpoint was ER-positive breast cancer-free survival. We examined 17 SNPs in these patients. The survival benefit associated with each genotype was determined with a log-rank test, and the hazard ratio was analyzed using a Cox proportional-hazards model. Results: The median follow-up time of the 320 patients enrolled on the study was 3298 days. Of 240 patients who received any endocrine therapy, ER-positive breast cancer-free survival in patients with the 2q35 rs13387042 AA genotype was significantly shorter than in those who had the AG or GG genotype (p < 0.0001), and the hazard ratio was significantly higher (HR 8.83; 95% CI 2.09–25.53, p = 0.0064). Of the 145 patients who received tamoxifen therapy, there was a trend among ER-positive breast cancer patients with the CYP2C19 rs4917623 TT genotype to have a shorter disease-free period (p = 0.0635) when compared to patients with TC or CC genotypes. Similarly, there was a trend for the TT genotype patients to exhibit a higher hazard ratio (HR 2.62; 95% CI 0.86–7.55, p = 0.0861). Conclusions: The rs4917623 SNP in the CYP2C19 gene, which encodes a metabolic enzyme, predicts tamoxifen efficacy. This finding will facilitate selection of ER-positive breast cancer patients for tamoxifen treatment; it may also be useful for selection of patients most likely to benefit from tamoxifen-dependent chemoprevention.

Abstract P1-15-04: Breast cancer recurrence and predictors for recurrence despite pathologic complete response following neoadjuvant chemotherapy

Abstract Introduction Breast cancer patients with a high-risk tumor (for example Triple Negative Breast Cancer) who achieve a pathological complete response (pCR) following neoadjuvant chemotherapy (NACT) have a better outcome compared to patients with residual disease at surgery. This study investigated Breast Cancer Free Survival (BCFS) and predictors for distant relapse despite pCR. Methods Monocentric retrospective study of 243 consecutive breast cancer patients who achieved pCR (ypT0/is ypN0/N0(i+)) after treatment with NACT in UZ Leuven between 01/2000 and 08/2017. 58% had stage III breast cancer, 40% Triple Negative Breast Cancer (TNBC) and 47% HER2 pos breast cancer. BCFS was defined as any breast cancer related event (local, contra-lateral, regional, metastatic) that first appeared. Primary endpoints were frequency of BCFS and predictors for metastatic relapse: patient demographics (age, body mass index (BMI)) and tumor characteristics (TNM stage, histological type, hormonal receptor status). Secondary endpoints were breast cancer specific survival (BCSS) and overall survival (OS). Statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS, version 25). The Kaplan Meier method was used for survival analysis. Results Of 1167 breast cancer patients undergoing neoadjuvant treatment, 243 patients (20,8%) achieved pCR and were included. Median follow up was 57 months (range 9-252 months). 22 (9.1%) developed tumor progression; 20 (8.2%) metastatic and 2 (0.8%) contralateral. First metastatic site was the brain in 11/20 patients (55%) and 14/22 (64%) died of breast cancer. Higher clinical tumor stage at diagnosis predicted metastatic relapse (stage I-II 2.9%; stage III 12.1%). Patients with a BMI ≤25 kg/m2 had less metastatic relapse than patients with BMI >25kg/m2 (3.8% versus 12.0%), better OS (94.6% vs 88.0%) and BCSS (97.7 vs 91.7%). Neither tumor type (TNBC 8.2%; HER2-pos 8.1%; HR-pos/HER2 neg 9.3%) nor younger age < 36yrs (3.3% versus 8.9%) was prognostic for post-pCR relapse. There is a lower OS (mean 174m versus 231m, 95% CI 158-190m, median 208m) and BCSS (mean 191m versus 253m, 95% CI 182-200m) in cN1-3 versus cN0 disease at diagnosis. Conclusion Despite NACT-induced pCR, a small proportion (9.1%) will develop a metastatic relapse after a median follow-up of 57 months. We found that a higher stage at diagnosis and a higher BMI were prognostic for worse BCFS while age <36 y and negative hormonal receptor status were not prognostic. cN+ at diagnosis and a BMI >25 predict worse OS and BCSS. Citation Format: Borremans K, Berteloot P, Van Nieuwenhuysen E, Han S, Hoste G, Wildiers H, Punie K, Smeets A, Nevelsteen I, Floris G, Van Ongeval C, Keupers M, Prevos R, Van Limbergen E, Menten J, Weltens C, Janssen H, Vergote I, Neven P. Breast cancer recurrence and predictors for recurrence despite pathologic complete response following neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-04.

Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms.

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis.

Screening BRCA1 and BRCA2 Mutation Carriers for Breast Cancer

Women with BRCA mutations, who choose to decline or defer risk-reducing mastectomy, require a highly sensitive breast screening regimen they can begin by age 25 or 30. Meta-analysis of multiple observational studies, in which both mammography and magnetic resonance imaging (MRI) were performed annually, demonstrated a combined sensitivity of 94% for MRI plus mammography compared to 39% for mammography alone. There was negligible benefit from adding screening ultrasound or clinical breast examination to the other two modalities. The great majority of cancers detected were non-invasive or stage I. While the addition of MRI to mammography lowered the specificity from 95% to 77%, the specificity improved significantly after the first round of screening. The median follow-up of women with screen-detected breast cancer in the above observational studies now exceeds 10 years, and the long-term breast cancer-free survival in most of these studies is 90% to 95%. However, ongoing follow-up of these study patients, as well of women screened and treated more recently, is necessary. Advances in imaging technology will make highly sensitive screening accessible to a greater number of high-risk women.

Prevalence and oncologic outcomes of BRCA 1/2 mutations in unselected triple-negative breast cancer patients in Korea.

Triple-negative breast cancer (TNBC) accounts for 10-20% of all diagnosed BCs and it is enriched in BRCA1 mutation. Guidelines for Western countries suggest that BRCA 1/2 genetic testing should be done for patients with TNBC diagnosed less than 60 years, but there is lack of evidence supporting genetic testing in Asian populations. We determined the prevalence of germline BRCA 1/2 mutations among unselected Korean patients with TNBC and analyzed oncologic outcomes. From among 1628 women with TNBC who underwent surgery at Samsung Medical Center (SMC) between Jul 2008 and Jan 2016, 999 samples were available in the SMC biobank for testing germline BRCA 1/2 mutations using next-generation DNA sequencing. Overall, 131 Korean patients (13.1%) had BRCA 1/2 mutations: 97 (9.7%) were in BRCA 1, and 35 (3.5%) were in BRCA 2. One patient had both BRCA 1 and BRCA 2 mutations. Overall, 68 distinct pathologic or likely pathogenic variants (43 BRCA1 and 25 BRCA2) were found. Among those diagnosed at ≤ 60 years, the prevalence of BRCA 1/2 mutation was 14.5%. The mean age of diagnosis of BRCA1/2 mutation carriers was significantly younger than that of non-carriers (45.6 vs. 50.1 years, p < 0.0001). The median follow-up duration was 53.6months. There were no significant differences in disease-free survival, overall survival, or breast cancer-specific survival (p = 0.799, 0.092, and 0.124, respectively) between BRCA 1/2 carriers and non-carriers, although BRCA 1/2 carriers showed significantly worse contralateral breast cancer-free survival (p < 0.0001) than non-carriers. In unselected TNBC patients, we found BRCA 1/2 mutations in 13.1% of overall patients and 14.5% of patients ≤ 60years. We suggest that Korean women with TNBC diagnosed at ≤ 60years should be tested for BRCA1/2 mutation.

Clinicopathological Characteristics and Outcomes of the Ongoing “Joven &amp; Fuerte” Cohort of Young Women With Breast Cancer in Mexico

Background: Despite high rates of breast cancer (BC) in young women from low and middle income countries, their needs and concerns are not systematically studied or addressed. Understanding the characteristics of young women with BC in limited-resource settings and the issues they face is of great relevance to the medical community, to tailor clinical interventions and supportive care for this unique and understudied patient population. The Mexican cohort Joven &amp; Fuerte has the goal of comprehensively characterizing and assessing the needs of YWBC in Mexico using patient- and physician-based surveys. Aim: The Mexican cohort Joven &amp; Fuerte has the goal of comprehensively characterizing and assessing the needs of YWBC in Mexico using patient- and physician-based surveys. Methods: A prospective cohort of newly diagnosed YWBC was established at the three Joven &amp; Fuerte sites. Eligible women answer electronic surveys on relevant topics, such as sociodemographic characteristics, fertility, genetics, and psychosocial needs, among others, while clinicians complete prespecified surveys registering clinicopathologic features and outcomes. Patients are evaluated at diagnosis, after 6 months, and annually for 5 years. Substudies assessing changes in cognition, sexual function and satisfaction, quality of life, and depression/anxiety are being carried out, and biologic samples are obtained and stored frozen for future research. Here, we report the baseline clinicopathological characteristics of patients included up to March 2018, as well as data on recurrence and mortality. Results: To date, 276 young women with BC with median age at diagnosis of 36 years (2140 y) have been accrued. 22% were single and 23%, childless. 42% had higher education and 31% were used. 80% presented with a self-detected mass. Clinical stage at diagnosis was distributed as follows: stage 0: 3%, I: 11%, IIA: 26%, IIB: 18%, III: 36%, and stage IV: 8%. The most frequent subtype was hormone-receptor (HR) pos/HER2 neg (52%), followed by triple neg (23%), HER2 pos/HR pos (17%) and HER2 pos/HR neg (8%). Histologic grade distribution among the patients was as follows: low grade (16%), intermediate grade (18%), and high grade (66%). Up to June 2017, 15 patients out of 120 (12.5%) have developed distant recurrences, and 12 patients (10%) have died as a consequence of breast cancer. With a median follow-up of 19 months, breast cancer free survival and overall survival was 87.7% and 89.9%, respectively. Conclusion: To our knowledge, this represents the first prospective cohort of young women with BC in Latin America. We are expanding this project to other centers in the region. Our findings will help develop culturally tailored interventions aimed at improving the medical and psychosocial outcomes of this vulnerable patient population.

Age exerts a continuous effect in the outcomes of Asian breast cancer patients treated with breast-conserving therapy

BackgroundAsians are diagnosed with breast cancer at a younger age than Caucasians are. We studied the effect of age on locoregional recurrence and the survival of Asian breast cancer patients treated with breast-conserving therapy.MethodsMedical records of 2492 patients treated with breast-conserving therapy between 1989 and 2012 were reviewed. The Kaplan–Meier method was used to estimate locoregional recurrence, breast cancer-free survival, and breast cancer-specific survival rates. These rates were then compared using log-rank tests. Outcomes and age were modeled by Cox proportional hazards. Fractional polynomials were then used to test for non-linear relationships between age and outcomes.ResultsPatients ≤ 40 years old were more likely to have locoregional recurrence than were older patients (Hazard ratio [HR] = 2.32, P < 0.001). Locoregional recurrence rates decreased year-on-year by 4% for patients with luminal-type breast cancers, compared with 8% for those with triple-negative cancers. Similarly, breast cancer-free survival rates increased year-on-year by 4% versus 8% for luminal-type and triple-negative cancers, respectively. Breast cancer-specific survival rates increased with age by 5% year-on-year. Both breast cancer-free survival and breast cancer-specific survival rates in patients with luminal cancers exhibited a non-linear (“L-shaped”) relationship—where decreasing age at presentation was associated with escalating risks of relapse and death. The influence of age on overall survival was confounded by competing non-cancer deaths in older women, resulting in a “U-shaped” relationship.ConclusionsYoung Asian breast cancer patients have a continuous year-on-year increase in rates of disease relapse and cancer deaths compared with older patients with no apparent threshold.

Propensity score to evaluate prognosis in pregnancy-associated breast cancer: Analysis from a French cancer network

PurposeTo compare the prognosis of pregnancy associated breast cancer occurring during pregnancy (BCP) to non-pregnancy associated breast cancers (non-BCP) in young women managed at a national expert center. MethodsRetrospective cohort study of a prospective database using propensity score matching (PSM) analysis with known prognostic factors. ResultsWe analyzed data of 49 patients with BCP and 104 with non-BCP diagnosed between 2002 and 2017 at Tenon University Hospital (Paris, France). The BCP tumors were often locally advanced (lymph node metastases in 59%), of high grade (55%) and highly proliferative (67% with Ki67 ≥ 20%). After PSM, breast cancer-free survival (p = 0.45) and breast cancer specific survival (p = 0.81) were similar in the two groups. The recurrence rate was 12% vs 18% (p = 0.45) and the death rate was 6% vs 8% (p = 0.74) for the BCP and non-BCP groups, respectively. No difference in recurrence type was observed between the groups (p = 0.60). ConclusionsAfter PSM for known prognostic factors, the prognosis of BCP patients did not differ from that of young patients with non-BCP.

Abstract P2-10-04: Targeted sequencing in early breast cancer: Identification of novel candidate mutations predictive of anthracycline benefit

Abstract Background The use of chemotherapies such as anthracyclines and taxanes have improved overall and disease free survival in breast cancer. For all patients, anthracyclines can have significant toxicities including cardiotoxicity and leukemia. It is therefore essential to select the subset of patients who will receive the optimal overall benefit from anthracycline therapy and to identify molecular pathways driving resistance. To fully understand the impact of mutations in the context of current breast cancer therapy, requires a comprehensive mapping of key molecular events in the context of treatment. We sequenced 101 genes, that were prioritized based on not only gene frequency, but also taking into account the importance of amino acid substitution, type of mutation and network connectivity, in 692 primary tumours to both identify driver genes and pathway cassettes and to understand their clinical significance in response to anthracycline treatment. Methods We performed targeted sequencing in patients from the BR9601 (n=374) and CCTG MA.5 (n=703) clinical trials. The BR9601 and MA.5 clinical trials examined the effectiveness of combination chemotherapy consisting of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) with or without epirubicin. DNA was extracted, samples were sequenced using AmpliSeq Technology adapted to Illumina and somatic mutations were called using a novel mutation calling pipeline (ISOWN). A priori analyses were performed using distant recurrence free survival (DRFS) as the primary endpoint. Results: In 692 successfully analysed samples 509 (73.6%) samples exhibited at least one single nucleotide mutation (range 0-54). 94/101 genes were mutated in at least one patient. Only variants in PIK3CA, TP53, CDH1, TLE6, MLL3 and USH2A were detected in 5% or more of samples. TSC22D1, RB1 and ZNF565 were associated with increased risk of distant relapse in multivariate analyses corrected for clinic-pathological variables. No single genes were predictive of anthracycline treatment compared to CMF in multivariate analyses corrected for clinic-pathological variables. Signaling cassettes/modules were designed based on the pathway database, Reactome. Within the signaling cassettes one module was predictive of anthracycline failure. Patients with one or more mutations in this module had an increased risk of distant relapse (HR 0.52, 95% CI 0.29-0.95, p=0.034) when treated with an anthracycline containing chemotherapy regimen compared to CMF (HR 1.34 95% CI 1.05-1.72, p=0.019). Conclusions: We successfully performed a signaling pathway-based targeted sequencing analysis within predefined signaling modules. We identified a single signaling cassette linked to anthracycline resistance in early breast cancer. However, further work to validate this study in a separate clinical trial is warranted. Citation Format: Spears M, Kalatskaya I, Trinh QM, Liao L, Chong TM, Crozier C, Dion D, Heisler L, Timms L, Stein LD, Pritchard KI, Levine MN, Shepherd L, Twelves CJ, Bartlett JMS. Targeted sequencing in early breast cancer: Identification of novel candidate mutations predictive of anthracycline benefit [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-04.

Abstract P2-10-01: Validation that a histone gene signature predicts anthracycline response in early breast cancer

Abstract Background: The use of anthracycline-based chemotherapies has improved overall and disease free survival in breast cancer. However, anthracyclines can have significant toxicities including cardiotoxicity and leukemia. It is, therefore, imperative to identify those patients who will benefit from adjuvant anthracycline treatment and patients who could be spared unnecessary toxicities and be considered for alternative adjuvant therapy. Previous work performed by our laboratory identified a histone gene expression signature as a predictive marker of anthracycline benefit in the BR9601 clinical trial. In this study we validate the 18 histone gene signature in the MA.5 clinical trial and examine the role of the signature in individual intrinsic subtypes of breast cancer. Methods We analysed the CCTG MA.5 clinical trial in a prospectively planned retrospective biomarker approach to validate this signature and tested the role of intrinsic subtyping as predictive markers of anthracycline benefit. RNA was extracted from patients in the MA.5 adjuvant trial evaluating the addition of epirubicin (E) to CMF and analysed using NanoString technology. Log-rank analyses validated the predictive values of the signature on distant relapse-free survival (DRFS). Cox-regression models tested independent predictive value on DRFS in the presence of treatment, age, tumour size, nodal status, HER2, ER status and grade, and treatment by marker interactions. Results Analysis of the MA.5 clinical cohort revealed that patients whose tumour had low histone gene signature expression experienced increased DRFS (HR: 0.54, 95% CI 0.38-0.76, p=0.001) when treated with CEF compared with patients treated with CMF alone. Conversely, there was no apparent benefit of CEF vs CMF in patients with high histone gene expression signature (HR: 1.01, 95%CI 0.66-1.55, p=0.963). After multivariate analysis and adjustment for HER2, nodal status, age, grade and ER, the treatment by marker interaction for the gene signature was 0.54 (95%CI 0.31-0.94, p=0.030) for DRFS. The predictive impact of the histone signature was independent of intrinsic subtype. Conclusion The histone gene expression signature is an independent predictor of anthracycline benefit and could be a potential candidate diagnostic assay for patients with early breast cancer. Citation Format: Spears M, Kornaga E, Lyttle N, Liao L, Bayani J, Quintayo M-A, Yao CQ, D'Costa A, Boutros PC, Twelves CJ, Pritchard KI, Levine MN, Nielsen TO, Shepherd L, Bartlett JMS. Validation that a histone gene signature predicts anthracycline response in early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-01.

Interactions between Alcohol Consumption and Adjuvant Hormone Therapy in Relation to Breast Cancer-Free Survival.

PurposeAlcohol consumption is associated with an increase in breast cancer risk, but findings on the association of alcohol with survival after breast cancer diagnosis have been inconsistent. Further, whether these associations could differ by adjuvant hormone therapy status is unknown. We examined interactions between alcohol consumption and adjuvant hormone therapy in relation to breast cancer-free survival among women with a primary breast cancer diagnosis.MethodsParticipants in this study included 1,399 women diagnosed with primary breast cancer between 2007 and 2012 at the Moffitt Cancer Center. Alcohol consumption during the year preceding diagnosis was assessed in a patient survey. Information on tumor characteristics, breast cancer treatment and outcomes was available from the Moffitt Cancer Registry. Associations were examined using Cox proportional hazards models in stratified analyses by adjuvant hormone therapy status, after adjustment for potential confounders.ResultsOverall, alcohol consumption was associated with significantly improved breast cancer-free survival (any vs. none: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65–0.92). Among women without adjuvant hormone therapy, alcohol consumption was associated with better survival in heavy drinkers (HR, 0.63; 95% CI, 0.43–0.93). Among women with adjuvant hormone therapy, survival was better in women consuming alcohol as compared to nondrinkers (moderate: HR, 0.69, 95% CI, 0.51–0.93; heavy: HR, 0.74, 95% CI, 0.57–0.96; any: HR, 0.71, 95% CI, 0.57–0.87). There was no significant interaction between alcohol and adjuvant hormone therapy (p-interaction=0.54 for alcohol modeled as none or any and p=0.34 for alcohol modeled as none, moderate, and heavy).ConclusionAssociations of alcohol consumption with breast cancer-free survival are similar in women with and without adjuvant hormone therapy. Future studies are warranted to elucidate potential mechanisms underlying the observed inverse associations.

Long-Term Follow-Up of the Intergroup Exemestane Study.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Abstract OT1-03-01: The UK LORIS trial: Randomizing patients with low or low intermediate grade ductal carcinoma in situ (DCIS) to surgery or active monitoring

Abstract Background: The independent review of the UK National Health Service Breast Screening Programme reported (The Lancet, Volume 380, Issue 9855, Page 1778, 17 Nov 2012) on the benefits and harms of breast screening. It concluded that breast screening saves lives and acknowledged the existence of overtreatment. It encouraged randomized trials to elucidate the appropriate treatment of screen-detected DCIS to gain a better understanding of its natural history. The LORIS trial addresses the possible overtreatment of low and low/intermediate grade screen-detected (low risk) DCIS by randomizing patients to standard surgical treatment or active monitoring, each with long term follow up. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year Feasibility Phase, in patients confirmed to have low risk DCIS defined by strict criteria and determined by central pathology review. Patients will be randomized between standard surgery and active monitoring with annual mammography. Patients will be followed up for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or ipsilateral DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients that do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival time Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of ipsilateral invasive breast cancer free survival (iiBCFS) time compared to treatment with surgery. The iiBCFS time will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α=0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm at 5 years, utilizing 80% power to exclude a difference of more than 2.5% in the active monitoring arm. Present Accrual and Target Accrual: 32 UK centres are open for the Feasibility Phase of the trial which is nearing completion. The web-based central pathology review process is functioning efficiently, with a one week maximum turn around. Registrations and sites randomizing patients are on or above target. Randomizations are currently approximately 70% of target. A total of 60 centres will open in the main trial. Contact Information: For further information, please email the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Format: Francis A, Bartlett J, Billingham L, Bowden S, Brookes C, Dodwell D, Evans A, Fairbrother P, Fallowfield L, Gaunt C, Hanby A, Jenkins V, Matthews L, Pinder S, Pirrie S, Rea D, Reed M, Roberts T, Thomas J, Wallis M, Wilcox M, Young J. The UK LORIS trial: Randomizing patients with low or low intermediate grade ductal carcinoma in situ (DCIS) to surgery or active monitoring [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-03-01.

Combined evaluation of the FAS cell surface death receptor and CD8+ tumor infiltrating lymphocytes as a prognostic biomarker in breast cancer.

Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.

Abstract OT2-02-04: The LORIS trial: A multicentre, randomised phase III trial of standard surgery versus active monitoring in women with newly diagnosed low risk ductal carcinoma in situ

Abstract Background: The independent review of the UK National Health Service Breast Screening Programme reported (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012) on the benefits &amp; harms of breast screening. It concluded that breast screening saves lives &amp; acknowledged overtreatment. It encouraged randomized trials to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) to gain a better understanding of its natural history. The LORIS trial addresses overtreatment of low &amp; low/Intermediate grade screen detected (low risk) DCIS by randomizing patients to standard surgical treatment or active monitoring. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a 2 year feasibility phase, in patients confirmed to have low risk DCIS by central pathology review. Patients are randomised to standard surgery or active monitoring with annual mammography. Patients will be followed up for a minimum of 10 years. Key Eligibility Criteria: 1) Female 46 years or over. 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) &amp; whether those patients that do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival rate at 5 years Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes &amp; health resource utilisation. A digital image data repository and tissue bank provide a prospective resource for both translational &amp; imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of 5 year ipsilateral invasive breast cancer free survival (iiBCFS) rate compared to treatment with surgery. The iiBCFS rate will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α=0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm giving 80% power to exclude a difference of more than 2.5% in the active monitoring arm at 5 years. Present Accrual and Target Accrual: 21 UK centres are open &amp; the feasibility phase of the trial is recruiting to target. The web based central pathology review process is functioning well with a one week maximum turn around. A further 40 centres will be opened on completion of the feasibility phase. Contact: LORIS@trials.bham.ac.uk This project was funded by the National Institute for Health Research [Health Technology Assessment Programme] (project number 11/36/16) Department of Health Disclaimer: The views &amp; opinions expressed therein are those of the authors &amp; do not necessarily reflect those of the Health Technology Assessment Programme, NIHR, NHS or the Department of Health. Citation Format: Francis A, Fallowfield L, Bartlett J, Thomas J, Wallis M, Hanby A, Pinder S, Evans A, Billingham L, Brookes C, Dodwell D, Fairbrother P, Gaunt C, Jenkins V, Matthews L, Pirrie S, Reed M, Roberts T, Wilcox M, Young J, Rea D. The LORIS trial: A multicentre, randomised phase III trial of standard surgery versus active monitoring in women with newly diagnosed low risk ductal carcinoma in situ. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-04.

Calpain-1 is associated with adverse relapse free survival in breast cancer: a confirmatory study.

Calpain-1 is a ubiquitously expressed calcium-activated intracellular cysteine protease. Altered expression of calpain system proteins has been implicated in cancer progression and response to chemotherapy. The aim of the current study was to confirm previous data that suggested that calpain-1 expression is associated with relapse-free survival in trastuzumab-treated breast cancer patients (n = 93). An expanded patient cohort from Nottingham (n = 194; including 72 of the previous cohort) and an independent patient cohort from Newcastle (n = 87) were used. All patients received trastuzumab following adjuvant therapy according to local guidelines with expression of calpain-1 investigated using standard immunohistochemistry. Results show that calpain-1 expression is associated with relapse-free survival in both the Nottingham (P = 0.01) and Newcastle (P = 0.019) cohorts, with high expression associated with adverse relapse-free survival. Expression was also associated with poor relapse-free survival when patient cohorts were combined (n = 281, P = 0.01). Calpain-1 remained, from multivariate analysis, an independent marker for relapse-free survival in the Newcastle cohort [hazard ratio (HR) = 5.169; 95% confidence interval (CI) 1.468-18.200; P = 0.011]. Calpain-1 expression is associated with poor relapse-free survival in breast cancer patients treated with trastuzumab. Further work is warranted to standardize and develop methodology with a view to potentially introducing assessment of this important biomarker into clinical practice.

AKAP3 correlates with triple negative status and disease free survival in breast cancer.

BackgroundCancer-testis antigens are among the new promising biomarkers, especially for targeted therapy. Aberrant and specific expression of these proteins has been reported in some tumor tissues. Also understanding their differential role in normal and cancer tissues may introduce them as new candidates for biomarker in cancer.MethodsAKAP3 expression was investigated in 162 tumors, normal adjacent and normal tissues of the breast with Real-Time PCR. Also the correlation between the gene expression and clinico-pathologic features of the tumors and treatment regimen was evaluated.ResultsThere was an association between lack of AKAP3 expression in tumor tissues and triple negative status (p=. 03). There was also a correlation between lack of this marker and tumor size (p = .01) and stage (p = .04). Lack of AKAP3 in normal adjacent tissues was associated with poor prognosis. Kaplan Meier plot demonstrated a remarkable better 5-year disease free survival in AKAP3 positive normal adjacent group.ConclusionsIt was found that this relationship is originated from the difference in AKAP3 expression, not therapy distribution between two groups of patients. Thus, it may be a proper biomarker candidate for triple negative breast cancer patients. Also, testing AKAP3 in normal tissue of the patients may be used to predict the outcome of the treatment.

439 Expression of the mTOR pathway genes as prognostic factors for distance recurrence free survival in breast cancer treated with neoadjuvant therapy

439 Expression of the mTOR pathway genes as prognostic factors for distance recurrence free survival in breast cancer treated with neoadjuvant therapy